Mood disorders, of which major depressive disorder is the most common, affect one person in five during their lifetime. The World Health Organization estimates that depression is currently the fourth most important worldwide cause of disability-adjusted life year loss, and that it will become the second most important cause by 2020 (See, Murray C J L and Lopez A D, The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability From Disease, Injuries, and Risk Factors in 1990 and Projected to 2020, volume 1. World Health Organization. Cambridge Ma.: Harvard University Press. 1996.). Pharmaceutical treatment of depression is frequently inadequate. In randomized clinical trials of the current best treatments, one-third of patients or more do not achieve remission, even after several months of treatment (See, Journal of the American Medical Association, 286:2947-55 (2001); Biological Psychiatry, 48:894-901 (2000)). Even when today's drugs do help patients achieve remission from their depression, the onset of action is over a period of weeks and there appears to be an increased risk of suicide during initial antidepressant therapy, although this risk may be less than that just prior to therapy initiation (See, Neuropsychopharmacology, 31:473-492 (2006)). Further, there are high recurrence rates—approximately 85% of patients who achieve remission will suffer another episode of major depression (See, American Journal of Psychiatry, 156:1000-6 (1999)). Finally, currently available antidepressants are associated with side effects that lead some patients to stop taking their medications at risk of sinking back (further) into depression, and to morbidity in others (See, New England Journal of Medicine, 353:1819-34 (2005)).
The currently available antidepressants work primarily by increasing the activity of certain neurotransmitters, serotonin and norepinephrine, in synapses. Some medications (such as monoamine oxidase inhibitors) inhibit the degradation of these molecules, others (such as selective serotonin reuptake inhibitors and dual serotonin/norepinephrine reuptake inhibitors) decrease removal of neurotransmitters from the synaptic space, and some medications (such as receptor antagonists) stimulate norepinephrine release or inhibit negative feedback of serotonin signaling. Because these medications are all based on a single principle, the strength and range of their efficacy is similar. The improvements of the last half century have involved the development of safer and more tolerable drugs. However, despite this, today's drugs are neither completely safe nor completely tolerable for many patients.
Thus, there is considerable need for new drugs that are effective in a broader range of patients (particularly for patients whose depression is resistant to available pharmaceuticals), that have a faster onset of action, that are safer and more tolerable, or that complement the efficacy of existing drugs. It is possible, but unlikely, that further improvement in any of these dimensions will be achieved through development of additional serotonergic or noradrenergic agents. Therefore, alternative pharmacological approaches must be developed and pursued.
Part of the challenge in developing new drugs lies in the complexity of demonstrating efficacy of a major depression treatment. For example, the development of novel antidepressants is constrained by the limited understanding of depression's etiology. Because of this, there are relatively few pharmacological targets that can be considered for antidepressant development. Thereupon, there is a need for the identification of drug targets for depression. Genetic linkage can open new windows for the development of novel depression drug targets. Specifically, if a genetic variant is identified as being linked to depression in families, the gene in which that variant occurs is likely to be involved in the etiology of disease. Such a gene can be a target for the development of novel antidepressants. Additionally, such a gene can lead to the identification of previously unknown physiological pathways that may be modulated for effective therapy of depression.
Several genes have been identified or proposed as factors for depression or related phenotypes. Among these, most have been associated with disease in population studies of candidate genes selected on the basis of existing hypotheses about the etiology of depression. Many of these genes relate to serotonin or norepinephrine. Examples include: (1) associations of a HTR1A (serotonin receptor 1A) promoter variant with depression, suicide, bipolar disorder, panic disorder with agoraphobia, neuroticism and anti-depressant response; (2) associations of the HTT (serotonin transporter) promoter short allele with depression, suicide, depressive behavior response to tryptophan depletion, bipolar disorder antidepressant-induced mania and lesser anti-depressant response; and (3) association of a variant in HTR2C (serotonin receptor 2C) with both recurrent major depression and bipolar disorder and with major depression.
Thereupon, as evidenced by the above, there is a need in the art to identify proteins and genes associated with the pathophysiology of depression that are proteins and genes that relate to other than serotonin or norepinephrine. Such proteins and genes would be useful in the diagnosis of depression or a related disorder, and in the development of new drugs that could be used to treat patients suffering from depression or a related disorder.